The present invention is related to pharmaceutical compositions and methods of treatment. More particularly it concerns pharmaceutical compositions comprising combinations of blood serum lipid and cholesterol regulating agents.
In recent years the role which elevated blood plasma levels of cholesterol plays in pathological conditions in man has received much attention. Deposits of cholesterol in the vascular system have been indicated as causative of a variety of pathological conditions including coronary heart disease.
Initially, studies of this problem were directed toward finding therapeutic agents which are effective in lowering total serum cholesterol levels. However, it has since been discovered that the mechanism by which cholesterol is transported in the blood and deposited as plaques on vascular walls is quite complex. Current understanding of the problem differentiates between the different forms of lipoprotein cholesterol which circulate in the blood stream and it is now believed that effective approaches to the control of blood serum cholesterol involve more than merely reducing the levels of total serum cholesterol.
For example, it is now known that cholesterol is transported in the bloodstream in the form of complex particles consisting of a core of cholesteryl esters or triglycerides and an surface coat consisting primarily of phospholipids, free cholesterol, several types of protein termed apolipoproteins which can be recognized by specific receptors. For example, cholesterol is carried to the sites of removal such as cells of the arterial wall in the form of low density lipoprotein cholesterol (LDL cholesterol) and away from such sites by high density lipoproteins. The LDL in peripheral cells is recognized by LDL receptors (or modified LDL receptors) and the HDL may be recognized by HDL receptors. Therefore, traffic in both directions depends upon apolipoprotein interactions.
Following these discoveries, the search for therapeutic agents which control serum cholesterol has increasingly turned to finding compounds which are more selective in their action; that is, agents which are effective both in elevating the serum levels of HDL cholesterol and/or lowering the levels of LDL cholesterol, and in lowering serum triglycerides.
One approach to lowering total and LDL-cholesterol levels in blood serum has centered around the discovery of therapeutic agents which inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). This enzyme is the rate-limiting step in the biosynthesis of cholesterol, and it is known that inhibitors of HMG-CoA reductase are effective in lowering the level of plasma cholesterol, especially LDL-cholesterol, in man (cf. M. S. Brown and J. L. Goldstein, New England Journal of Medicine, 305 (9): 515-517 (1981).
In an alternative approach to the control of serum lipoproteins and cholesterol, it has been found that 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid (commonly known as gemfibrozil) acts to elevate plasma levels of HDL-cholesterol and to decrease plasma triglycerides. This pharmacological action is an effective method of treating a variety of primary and secondary dislipoproteinemias. (See Saku et al., J. Clin. Invest., 75: 1702-1712 (1985)).
Agents which lower serum cholesterol levels also tend to raise the concentrations of cholesterol found in bile, since the conversion of cholesterol to bile acids is one mechanism by which the body eliminates cholesterol.
Gemfibrozil has been shown to be effective in increasing the amount of cholesterol excreted in to bile. (See Ottmar Leiss et al., Metabolism, 34 (1): 74-82 (1985).
Likewise the fibric acid derivatives such as clofibrate (i.e. 2-(4-chlorophenoxy)-2-methylpropanoic acid, ethyl ester), bezafibrate (i.e. 2-[4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy]-2-methylpropanoic acid), and fenofibrate (i.e. 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid, 1-methylethyl ester) are effective in increasing the concentrations of biliary cholesterol. (See S. M. Grundy et al., J. Lipid Res., 13: 531-551 (1972); D. Pertsemlidis et al., Gastroenterology, 66: 565-573 (1974); and K. von Bergmann et al., Europ. J. Clin. Invest., 14: 150-154 (1984)).
Bile acid sequestering agents such as cholestipol and cholestyramine lower plasma cholesterol by sequestering bile acids in the intestinam lumen. The net result is the up-regulation of liver LDL receptors as occurs with HMG-CoA reductase inhibitors.
While each of the foregoing types of cholesterol-controlling agents are effective in moderating the levels of serum cholesterol and triglycerides, or increasing the concentrations of biliary cholesterol, they have little or no direct effect on controlling the initial adsorption of dietary cholesterol in the body through the intestinal wall or the reabsorption of cholesterol from the bile in the intestine.
In intestinal mucosal cells, dietary cholesterol is absorbed as free cholesterol which must be esterified by the action of the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) before it can be packaged into the chylomicrons which are then released into the blood stream. Thus, therapeutic agents which effectively inhibit the action of ACAT prevent the intestinal absorption of dietary cholesterol or the reabsorption of cholesterol which has been previously released into the intestine through the biliary system.
Some attempts have been made to find effective combinations of therapeutic agents to control serum cholesterol and lipid levels. U.S. Pat. No. 3,846,541 discloses the coadministration of chlorophenoxy isobutyric acid and its esters with a bile acid sequestering agent. Such combinations result in some lowering of low-density and total cholesterol, but result in compensatory increases in cholesterol biosynthesis.
European Patent Application 0 010 299 discloses combinations of HMG-CoA reductase inhibitors and bile acid sequestrants which are effective in lowering LDL-cholesterol but have minimal effect on HDL-cholesterol.